The effect of multiple SNPs in ABCB1 gene on its expression and clinico-pathological characteristics in breast cancer patients

A81 Multidrug resistance of tumor cells to cytotoxic drugs is one of the major impediments in successful cancer chemotherapy. A significant part of tumor resistance to chemotherapy is caused by ABC transporter P-glycoprotein (P-gp, encoded by ABCB1 gene). High expression of ABCB1 and its genetic variations (e.g. SNPs) thus may have a great clinical impact. The aim of this study was to investigate the relationship between multiple ABCB1 SNPs, the expression level of the gene and prognosis of patients with breast carcinomas. Analyses of 7 ABCB1 SNPs and expression levels in 90 sets of samples from breast cancer patients were performed. ABCB1 genotype was assayed with a novel method that allows simultaneous assessment of multiple SNPs in numerous samples on a single Nanogen electronic microarray platform. The distribution of ABCB1 genotype in breast cancer cases was compared with the distribution in 100 healthy controls. ABCB1 expression was quantified in cDNA samples from tumor and non-tumor tissues of breast cancer patients by real-time PCR. Both ABCB1 SNPs and expression levels were correlated with clinico-pathological characteristics to answer the prognostic value of ABCB1 genotypes and/or phenotypes in breast cancer. ABCB1 was expressed in 87/88 (98.9 %) of tumor and in 39/40 (97.5%) of non-tumor samples. A striking inter-individual variability in expression of ABCB1 was found. ABCB1 was down-regulated in 89.7% of all tumors. No significant correlation between ABCB1 expression and any clinico-pathological dates was observed. High frequencies of variant alleles in ABCB1 exon 12 (1236C>T, qT = 38.3), exon 21 (2677G>T/A, qT = 40.0, qA = 6.7) and exon 26 (3435C>T, qT = 54.0) were revealed. Individuals with variant alleles in these three SNPs had a significantly lower ABCB1 expression in their tumors than patients with normal genotype. SNPs in exon 12, exon 21 and exon 26 also correlated with estrogen receptor status of patients. Thus these SNPs may affect function of P-gp and modify breast cancer prognosis.
 > This work was supported by grants of Grant Agency of the Czech Republic 305/07/P347, Internal Grant Agency of the Czech Ministry of Health, no.: 9426-3 and the National Program FUGE no.: 151924/150 and 15204/150, funded by The Research Council in Norway.